Infectious disease

Cell culture and in vitro studies identified phenylpyrrolidine-based inhibitors of CYPA, CYPB and CYPD that could help treat HCV, HIV/AIDS, coronavirus and other viral infections. In silico screening of a fragment library against the CYPD active site followed by chemical synthesis and testing of hits in enzyme activity assays identified 10 compounds containing a phenylpyrrolidine scaffold that inhibited CYPA, CYPB and CYPD with IC₅₀ values of 0.1-13.1, 0.08-8.7 and 0.2-12.8 µM, respectively. In a human liver cell line-based HCV replicon assay, seven of the compounds decreased replication with EC₅₀ values of 0.4-8.4 µM. In human leukemia cells infected with HIV, four of the compounds decreased viral replication with EC₅₀ values of 3.6-15 µM. In a human fibroblast cell line infected with human coronavirus, seven of the compounds decreased viral replication with EC₅₀ values of 7.2-71.5 µM. Next steps include testing the compounds in animal models of viral infection.

Scynexis Inc. and Waterstone Pharmaceuticals Ltd. have SCY-635, a cyclophilin inhibitor, in Phase II testing to treat HCV...